U.S. patent application number 13/706668 was filed with the patent office on 2013-06-13 for bio-diagnostic testing system and methods.
This patent application is currently assigned to SANOFI AVENTIS. The applicant listed for this patent is CALIFORNIA INSTITUTE OF TECHNOLOGY, Sanofi Aventis. Invention is credited to Remi BROUARD, III, Jingqing HUANG, Emil P. KARTALOV, Axel SCHERER.
Application Number | 20130149714 13/706668 |
Document ID | / |
Family ID | 48572313 |
Filed Date | 2013-06-13 |
United States Patent
Application |
20130149714 |
Kind Code |
A1 |
SCHERER; Axel ; et
al. |
June 13, 2013 |
BIO-DIAGNOSTIC TESTING SYSTEM AND METHODS
Abstract
An implantable diagnostic device in accordance with the present
disclosure includes a probe assembly that can be implemented in a
variety of ways. A few example implementations include: a needle
inside which is located a bio-sensor chip (the needle being
insertable into a human being); a compact package containing the
bio-sensor chip (the compact package configured for placement
inside a catheter); or a silicon-based bio-sensor package
configured for insertion into a vein.
Inventors: |
SCHERER; Axel; (Barnard,
VT) ; BROUARD, III; Remi; (San Francisco, CA)
; KARTALOV; Emil P.; (Los Angeles, CA) ; HUANG;
Jingqing; (Pasadena, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CALIFORNIA INSTITUTE OF TECHNOLOGY;
Sanofi Aventis; |
Pasadena
Paris |
CA |
US
FR |
|
|
Assignee: |
SANOFI AVENTIS
Paris
CA
CALIFORNIA INSTITUTE OF TECHNOLOGY
Pasadena
|
Family ID: |
48572313 |
Appl. No.: |
13/706668 |
Filed: |
December 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61568008 |
Dec 7, 2011 |
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Current U.S.
Class: |
435/7.4 ;
436/501; 600/301; 600/318; 600/341; 600/342; 600/343 |
Current CPC
Class: |
A61B 5/14507 20130101;
A61B 5/1459 20130101; A61B 5/7278 20130101; A61B 5/0002 20130101;
A61B 2560/0233 20130101; A61B 5/1491 20130101; A61B 3/10 20130101;
A61B 5/6848 20130101; A61B 5/4337 20130101; A61B 5/01 20130101;
A61B 5/418 20130101; A61B 5/6866 20130101; A61B 5/20 20130101; A61B
5/14546 20130101; A61B 5/1451 20130101; A61B 5/6852 20130101; A61B
5/42 20130101; A61B 2560/0219 20130101 |
Class at
Publication: |
435/7.4 ;
436/501; 600/342; 600/341; 600/318; 600/343; 600/301 |
International
Class: |
A61B 5/1459 20060101
A61B005/1459; A61B 5/145 20060101 A61B005/145; A61B 5/01 20060101
A61B005/01; A61B 5/20 20060101 A61B005/20; A61B 5/1491 20060101
A61B005/1491; A61B 3/10 20060101 A61B003/10; A61B 5/00 20060101
A61B005/00 |
Claims
1. A bio-diagnostic system comprising: a probe assembly configured
for insertion into an animate object, the probe assembly
comprising: an optical waveguide configured for propagating a light
beam; and an optical resonator incorporating a capture agent placed
upon a binding site that is exposed to a fluid, the optical
resonator configured to receive at least a portion of the
propagated light beam and generate therefrom, a first resonant
wavelength when no binding reaction is present at the binding site,
and a second resonant wavelength when a binding reaction is present
at the first binding site, the binding reaction modifying a
refractive index of the optical resonator.
2. The bio-diagnostic system of claim 1, wherein the probe assembly
is at least one of: a) a needle comprising a first bio-sensor chip
that includes the optical waveguide and the first optical
resonator, b) a catheter comprising a second bio-sensor chip that
includes the optical waveguide and the first optical resonator, or
c) a third bio-sensor chip configured for insertion into the vein,
the third bio-sensor chip comprising the optical waveguide and the
first optical resonator.
3. The bio-diagnostic system of claim 2, wherein at least one of
the needle or the catheter is a part of an intravenous (IV)
apparatus.
4. The bio-diagnostic system of claim 2, wherein the needle has a
sub-mm diameter.
5. The bio-diagnostic system of claim 4, wherein the fluid is one
of: blood, lymphatic fluid, cerebrospinal fluid, urine, saliva,
vaginal fluid, gall, digestive fluid, or ocular fluid.
6. The bio-diagnostic system of claim 4, wherein the probe assembly
is configured for detecting an analyte at an in-vivo location, the
in-vivo location comprising at least one of: i) a location inside a
blood vessel, ii) a location outside a blood vessel, iii) a
location inside a lymphatic vessel, iv) a location outside a
lymphatic vessel, v) a location inside tissue, or vi) a location
outside tissue.
7. The bio-diagnostic system of claim 6, wherein the analyte is
detected in at least one of: 1) blood flowing in one of a vein or
an artery, or 2) lymphatic fluid in a lymphatic vessel.
8. The bio-diagnostic system of claim 4, further comprising: a
light source for injecting light at near-infrared wavelength into
the optical waveguide.
9. The bio-diagnostic system of claim 8, wherein the light source
is a near-infrared communications laser, and further wherein each
of the first, the second and the third bio-sensor chips further
includes a detector for generating a first electrical output signal
upon detection of the first resonant wavelength and a second
electrical output signal upon detection of the second resonant
wavelength.
10. The bio-diagnostic system of claim 9, wherein each of the
first, the second and the third bio-sensor chips further includes:
a heating element configured for heating the first binding site;
and a calorimeter for measuring a temperature of the first binding
site.
11. A bio-diagnostic system comprising: a probe assembly configured
for detecting at least one target molecule in a fluid that makes
flowing contact with the probe assembly, the probe assembly
comprising: an optical waveguide configured for propagating a light
beam; and an optical resonator incorporating a capture agent placed
upon a binding site that is exposed to the at least one target
molecule, the optical resonator configured to receive at least a
portion of the propagated light beam and generate therefrom, a
first resonant wavelength when no binding reaction is present at
the binding site, and a second resonant wavelength when a binding
reaction is present at the first binding site, the binding reaction
modifying a refractive index of the optical resonator.
12. The bio-diagnostic system of claim 11, wherein the probe
assembly includes at least one of: a) a needle comprising a first
bio-sensor chip that includes the optical waveguide and the first
optical resonator, b) a catheter comprising a second bio-sensor
chip that includes the optical waveguide and the first optical
resonator, or c) a silicon-based probe assembly configured for
insertion into the vein, the silicon-based probe assembly
comprising the optical waveguide and the first optical
resonator.
13. The bio-diagnostic system of claim 11, further comprising: a
light source for injecting light at near-infrared wavelength into
the optical waveguide.
14. The bio-diagnostic system of claim 13, wherein the at least one
molecule is a short-lived molecule present in at least one of: a)
blood, or b) a dialysate.
15. The bio-diagnostic system of claim 14, wherein the probe
assembly is incorporated into a catheter that is a part of at least
one of: a) an intravenous (IV) system, or b) a dialysis
apparatus.
16. The bio-diagnostic system of claim 13, wherein the probe
assembly is configured as one of: a) a needle, b) a catheter, or c)
an object that is insertable onto a tube transporting the
fluid.
17. A method of using a bio-diagnostic system, comprising:
inserting a first probe assembly into at least one of: a) a first
conduit that is propagating a fluid containing at least one target
molecule, or b) an animate object, the first probe assembly
comprising a bio-sensor chip incorporating an optical waveguide and
an optical resonator containing a capture agent placed at a binding
site in the optical resonator; propagating light through the
optical waveguide; coupling at least a portion of the light from
the optical waveguide into the optical resonator; generating in the
optical resonator, a first resonant wavelength when no binding
reaction is present at the binding site; generating in the optical
resonator, a second resonant wavelength when a refractive index of
the optical resonator is modified as a result of a first binding
reaction at the binding site, the first binding reaction
characterized by the at least one target molecule binding to the
capture agent; and deriving information pertaining to the at least
one target molecule upon detecting the change from the first
resonant wavelength to the second resonant wavelength.
18. The method of claim 17, wherein the first conduit is a first
tube of a dialysis apparatus, and further comprising: inserting a
second probe assembly into a second tube of the dialysis apparatus;
deriving information pertaining to another at least one target
molecule propagating through the second tube; and analyzing the
fluid by using at least one of a) the derived information
pertaining to the at least one target molecule, or b) the derived
information pertaining to the another at least one target
molecule.
19. The method of claim 17, wherein the first probe assembly is
incorporated into a catheter, and inserting the first probe
assembly into the animate object comprises inserting a portion of
the catheter into at least one of: a) a peritoneal cavity of an
animal, or b) a rectouterine pouch of the animal.
20. The method of claim 19, further comprising: retaining the
portion of the catheter in the one of the peritoneal cavity or the
rectouterine pouch for over a day.
21. The method of claim 20 wherein the portion of the catheter is
retained in the one of the peritoneal cavity or the rectouterine
pouch for at least one year.
22. The method of claim 17, wherein the first conduit is one of a)
a vein propagating blood or b) a tube propagating an intravenous
(IV) fluid.
23. The method of claim 22, wherein deriving information pertaining
to the at least one target molecule comprises deriving information
pertaining to a plurality of different types of target
molecules.
24. The method of claim 22, wherein deriving information pertaining
to the at least one target molecule comprises information
pertaining to only a first type of target molecule.
25. The method of claim 22, further comprising: heating the binding
site to derive thermal characteristics of the at least one target
molecule.
26. The method of claim 25, wherein heating the binding site
comprises heating the binding site over a period of time for
deriving thermal characteristics over the period of time.
27. The method of claim 22, further comprising: heating the binding
site to desorb the at least one target molecule from the capture
agent and prepare the binding site for a second binding reaction.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional
Application 61/568,008 filed on Dec. 7, 2011, entitled "Intravenous
Protein Detector Using Optical Resonators," which is incorporated
herein by reference in its entirety.
FIELD
[0002] The present teachings relate to diagnostic devices that are
configured for making contact with a flowing fluid such as blood,
for carrying out diagnostic tests. More specifically, the present
disclosure relates to a probe assembly that includes an optical
resonator and circuitry for performing bio-diagnostic tests upon
flowing fluids.
BACKGROUND
[0003] Bio-diagnostic testing, such as blood tests, are typically
performed using on-site or off-site large-scale automated
instruments geared towards efficient processing of large batches of
prepared fluid samples. However, this type of set-up is not very
suitable for emergency care treatment requiring fast turnaround in
testing or continuous monitoring of fluids. For example, existing
large-scale automated instruments are unsuitable for continuous
in-vivo protein measurements upon a patient in an intensive care
unit.
[0004] Furthermore, treatment of serious cardiovascular conditions,
such as myocardial infarction or stroke with anticoagulants or
antiplatelet drugs requires accurate and rapid feedback from blood
chemistry tests performed upon patients. For such situations, as
well as for other situations where for example short-lived proteins
are to be measured, it is desirable to provide for improved devices
and methods of bio-diagnostic testing.
SUMMARY
[0005] According to a first aspect of the present disclosure, a
bio-diagnostic system includes a probe assembly configured for
insertion into an animate object. The probe assembly includes an
optical waveguide configured for propagating a light beam; and
further includes an optical resonator incorporating a capture agent
placed upon a binding site that is exposed to a fluid. The optical
resonator is configured to receive at least a portion of the
propagated light beam and generate therefrom, a first resonant
wavelength when no binding reaction is present at the binding site,
and a second resonant wavelength when a binding reaction is present
at the first binding site, the binding reaction modifying a
refractive index of the optical resonator.
[0006] According to a second aspect of the present disclosure, a
bio-diagnostic system includes a probe assembly configured for
detecting at least one target molecule in a fluid that makes
flowing contact with the probe assembly. The probe assembly
includes an optical waveguide configured for propagating a light
beam, and further includes an optical resonator incorporating a
capture agent placed upon a binding site that is exposed to the at
least one target molecule. The optical resonator is configured to
receive at least a portion of the propagated light beam and
generate therefrom, a first resonant wavelength when no binding
reaction is present at the binding site, and a second resonant
wavelength when a binding reaction is present at the first binding
site, the binding reaction modifying a refractive index of the
optical resonator.
[0007] According to a third aspect of the present disclosure, a
method of using a bio-diagnostic system, includes: i) inserting a
first probe assembly into at least one of: a) a first conduit that
is propagating a fluid containing at least one target molecule, or
b) an animate object, the first probe assembly comprising a
bio-sensor chip incorporating an optical waveguide and an optical
resonator containing a capture agent placed at a binding site in
the optical resonator; ii) propagating light through the optical
waveguide; iii) coupling at least a portion of the light from the
optical waveguide into the optical resonator; iv) generating in the
optical resonator, a first resonant wavelength when no binding
reaction is present at the binding site; v) generating in the
optical resonator, a second resonant wavelength when a refractive
index of the optical resonator is modified as a result of a first
binding reaction at the binding site, the first binding reaction
characterized by the at least one target molecule binding to the
capture agent; and vi) deriving information pertaining to the at
least one target molecule upon detecting the change from the first
resonant wavelength to the second resonant wavelength.
[0008] Further aspects of the disclosure are shown in the
specification, drawings and claims of the present application.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The accompanying drawings, which are incorporated into and
constitute a part of this specification, illustrate one or more
embodiments of the present disclosure and, together with the
description of a few example embodiments, serve to explain the
principles and implementations of the disclosure. The components in
the drawings are not necessarily drawn to scale. Instead, emphasis
is placed upon clearly illustrating various principles. Moreover,
in the drawings, like reference numerals designate corresponding
parts throughout the several views.
[0010] FIG. 1 shows a bio-diagnostic testing system that includes a
laser source and a probe assembly in accordance with the present
disclosure.
[0011] FIG. 2 shows an alternative embodiment of a bio-sensor chip
shown as a part of the probe assembly in FIG. 1.
[0012] FIG. 3 shows a first example embodiment of a probe assembly
in accordance with the present disclosure.
[0013] FIG. 4 shows a second example embodiment of a probe assembly
in accordance with the present disclosure.
[0014] FIG. 5 shows a third example embodiment of a probe assembly
in accordance with the present disclosure.
[0015] FIG. 6 shows an example bio-diagnostic testing application
in accordance with the present disclosure.
DETAILED DESCRIPTION
[0016] Throughout this description, embodiments and variations are
described for the purpose of illustrating uses and implementations
of the inventive concept. The illustrative description should be
understood as presenting examples of the inventive concept, rather
than as limiting the scope of the concept as disclosed herein.
Furthermore, the use of certain words and/or phrases should be
understood in the context of the description and it should be
understood that in some instances alternative words or phrases may
be used to refer to substantially similar actions or elements. As
one example of such usage, it should be understood that phrases
such as a binding site or an immunoassay site generally refer to a
location in an optical isolator wherein a binding agent (referred
to herein variously as a capture agent or an aptamer) is placed in
order to provide a binding mechanism for binding an object of
interest (referred to herein variously as molecule, a foreign
molecule, a target molecule, or a protein). The use of such words
will be understood in a broad sense by persons of ordinary skill in
the art and should not be construed as limiting or exclusionary in
nature. It will be further understood that the word "in-vivo" is
intended to indicate that the probe assembly of the bio-diagnostic
system disclosed herein can be implanted inside animate objects.
(The phrase "animate object" as used herein in the disclosure
represents a wide variety of living objects, such as for example,
human beings, animals, mammals, vertebrates, invertebrates, avian
species fish, fowl, etc. etc.) However, nothing precludes the
bio-diagnostic system from being configured and/or used in various
applications outside a living object. For example, the
bio-diagnostic system in accordance with the disclosure can be used
for carrying out tests (such as an assay test using a hand-held
apparatus) for purposes of analyzing a flowing fluid. In some
implementations that may not be necessarily viewed as in-vivo
applications, the probe assembly described herein may be located in
one or more fluid carrying tubes (an intravenous (IV) tube, for
example) connected to a living entity, such as a human patient.
[0017] In general, when used for in-vivo applications, the
bio-diagnostic system in accordance with the disclosure can be used
to detect and/or to measure analytes present in various kinds of
fluids; and in various locations inside an animate object. Some
non-limiting examples of the various kinds of fluids include:
blood, lymphatic fluid, cerebrospinal fluid, urine, saliva, vaginal
fluid, gall, digestive fluids, ocular fluids etc. Some non-limiting
examples of the various locations inside an animate object include
locations inside various organs and tissues, as well as locations
on the outside of various organs and tissues (such as, for example,
on the outside surface of a vein, or in the vicinity of lung
tissue).
[0018] The various embodiments described herein are generally
directed at a bio-diagnostic system that includes a probe assembly.
The probe assembly may be implemented in a variety of ways. A few
example implementations include: a needle inside which is located a
bio-sensor chip (the needle being insertable into a human being); a
compact package containing the bio-sensor chip (the compact package
configured for placement inside a catheter or for in-vivo
applications); or a silicon-based bio-sensor package configured for
insertion into a vein.
[0019] More particularly, a diagnostic system in accordance with
the present disclosure includes a probe assembly that incorporates
a bio-sensor chip fabricated in silicon. The probe assembly can be
used for label-free identification of binding reactions in
real-time, in in-vivo environments, as well as in various other
environments wherein testing can be carried out on flowing fluids.
The testing procedures and devices disclosed herein provide
significantly higher sensitivity than those obtained using
conventional immunoassay and ELISA techniques. These, and other,
features of the bio-diagnostic system will be described below in
further detail using the various figures.
[0020] Attention is first drawn to FIG. 1, which shows a
bio-diagnostic system 100 that includes a light source 105 and a
probe assembly 150 in accordance with the present disclosure. Light
source 105 can be implemented via a variety of commercially
available devices. For example, light source 105 can be a
near-infrared communications laser system that generates a laser
beam at near-infrared wavelengths. The laser beam can be coupled
into probe assembly 150 using an optical fiber or other suitable
communication media.
[0021] Probe assembly 150 can be implemented in various ways, some
of which will be described below in more detail using other
figures.
[0022] In the example bio-diagnostic system 100 shown in FIG. 1,
probe assembly 150 is depicted as a needle 155 housing a bio-sensor
chip 110 inside. The dimensions of needle 155 can vary depending on
various operating environments. In one example implementation,
needle 155 has a sub-mm diameter. Needle 155 can be composed of any
material that is ordinarily used for hypodermic applications, such
as, for example, stainless steel, or can be composed of certain
non-traditional materials. As for non-traditional materials, in one
embodiment described below in more detail, needle 155 is composed
of a silicon material.
[0023] It should be understood that needle 155 can propagate a
fluid in either direction depending for example, on the nature of
use of a piston mechanism (not shown). Specifically, fluid flow in
a first direction can correspond to using needle 155 for drawing
blood, for example, while fluid flow in the opposite direction can
correspond to injecting a medication into a patient, for example.
The piston mechanism used in hypodermic syringes is known to
persons of ordinary skill in the art and will not be described
herein so as to avoid distracting from certain primary aspects of
the disclosure.
[0024] Irrespective of the direction of fluid flow, bio-sensor chip
110 is arranged so as to be exposed to flowing fluid in order to
allow one or molecules to make contact and undergo a binding
reaction in an optical resonator. The binding reaction is detected
via a change in resonant wavelength in the optical resonator and
interpreted accordingly so as to derive information about a
molecular content of the flowing fluid. For example, when needle
155 is inserted into a vein of a human being, bio-sensor chip 110
can be used to quantify intravenous thrombin levels in blood. Using
probe assembly 150, and more particularly, needle 155, in this
manner provides thrombin related information on "fresh blood" that
is circulating in a vein rather than on extracted blood (as in
prior art in-vitro testing), thereby providing measurements that
accurately reflect clinically relevant thrombin levels. It will be
understood that probe assembly 150 (in the various embodiments
described herein) can be implanted/inserted into various types of
fluid-carrying elements, both natural as well as man-made. A few
examples of natural fluid-carrying elements include: a vein, an
artery, a lymphatic vessel, a tissue, or an organ such as the brain
for example, while a few examples of man-made fluid-carrying
elements include: a catheter and an IV tube.
[0025] Furthermore, in contrast to the measuring techniques and
devices described herein, prior art techniques that incorporate
electrical measurements would be difficult to adapt for a "back
end" detection process because ion and cholesterol concentrations
in blood would interfere with the electrical measurements.
[0026] Another advantage of the measuring techniques and devices
described herein arises from the fact that the measurement devices
provide high temperature durability; a significant shelf life
without deterioration; and permit measurements without swapping out
devices for a significant period of time. Such features are
advantageous for use in various measurement environments such as an
operating theater, or an extensive care ward of a hospital.
[0027] Needle 155 houses a bio-sensor chip 110 that contains an
optical waveguide 120 for propagating a laser beam injected into
probe assembly 150 when light source 105 is a coherent light
source. In contrast to probe assembly 150, which is designed for
various in-vivo environments, light source 105 is typically located
outside an animal or human being. However, in certain embodiments,
light source 105 may be configured for insertion into the animal or
human being, either as an integrated package that contains both
light source 105 as well as probe assembly 150; or as a separate
first package containing light source 105, with the first package
coupled to a second in-vivo package containing bio-sensor chip
110.
[0028] A portion of the coherent light beam injected by light
source 105 into optical waveguide 120 is diverted from the main
light beam path 121 as an auxiliary light beam that is coupled into
optical resonator 130 via an auxiliary light beam path 122. The
diversion may be carried out in a variety of ways. For example, in
a first implementation, coupler/switch 115 is a coupler that taps
into the main light beam path 121 to access a portion of the light
beam. In a second implementation, coupler/switch 115 is an optical
switch that diverts all or a portion of the coherent light beam
from main light beam path 121 into auxiliary light beam path 122.
Optical couplers and optical switches are known in the art, and
will not be elaborated upon herein so as to avoid detracting from
the primary focus of the present disclosure.
[0029] The coherent light beam propagated via auxiliary light beam
path 122 is coupled into optical resonator 130 where the beam is
circulated (as indicated by arrow 123) in order to generate a
resonant wavelength. Optical resonator 130 is shown in FIG. 1 as a
circular resonator, but it should be understood that optical
resonator 130 may be implemented in a variety of ways, including
resonators having a non-circular structure.
[0030] Auxiliary light beam path 122 that is coupled into optical
resonator 130 is directed into an optical resonant cavity, for
example, a "whispering gallery" structure (not shown) that is known
in the prior art. In general, when broad spectrum light is
introduced into an optical resonant cavity, only specific
wavelengths, referred to herein as resonant wavelengths, are
reinforced inside the optical resonant cavity as a result of
constructive interference. The resonant wavelengths are determined
on the basis of a length of an optical path in a waveguide
structure of the optical resonant cavity (for example, a length of
the propagation path in a whispering gallery). More specifically,
resonant wavelengths are determined on the basis of optical path
lengths configured in accordance to integer multiples of the
respective half-wavelengths of the resonant wavelengths.
[0031] In the present disclosure, optical resonator 130 provides
for at least two resonant wavelengths. The first resonant
wavelength is determined by a first optical characteristic of
optical resonator 130, particularly, in terms of a first optical
signal path length, an absorption parameter, and/or a first
refractive index of the optical signal path length. One or more of
these parameters are defined in part by a binding site 133. Binding
site 133, which is located upon an internal surface of the optical
resonant cavity of optical resonator 130, contains a capture agent
132 (an aptamer, for example). Capture agent 132 is selectively
located on the internal surface in a manner that facilitates a
foreign molecule 131 (alternatively referred to herein as a
"target" molecule) from binding to capture agent 132. The foreign
molecule 131 may be a target molecule, such as a thrombin molecule,
flowing in a blood stream of a human being. Further details
pertaining to this topic will be provided below.
[0032] The first resonant wavelength is defined when no foreign
molecule 131 is bound to capture agent 132 present at binding site
133.
[0033] In contrast, a second resonant wavelength is defined when a
foreign molecule 131 is present at binding site 133. The presence
of the foreign molecule 131 at binding site 133 modifies the
refractive index of the first optical signal path, thereby changing
the first resonant wavelength to the second resonant
wavelength.
[0034] The shift from the first resonant wavelength to the second
resonant wavelength provides an indication that foreign molecule
131 is present at binding site 133. In other words, bio-sensor chip
110 uses the resonant wavelength shift for detecting an occurrence
of a bio-molecular binding. Such a wavelength-oriented detection
process not only provides high detection sensitivity in probe
assembly 150 but also provides additional advantages. For example,
probe assembly 150 in accordance with the disclosure can be used
for re-usable, label-free bio-molecular detection in real time or
near-real time (at millisecond intervals, for example).
[0035] Bio-sensor chip 110 further includes a detector 140, which,
in contrast to expensive, complex and bulky prior art detection
devices, can be fabricated on silicon inside the same package
containing optical resonator 130, thereby providing various
advantages such as compact size, low cost, and high detection
sensitivity.
[0036] Detector 140 is basically an optical-to-electrical converter
(O/E converter) that accepts light provided out of optical
resonator 130, and generates an electrical signal, say in the form
of a detector current. More specifically, detector 140 generates a
first electrical signal (say, a first detector current) in response
to light provided by optical resonator 130 at the first resonant
wavelength, and generates a second electrical signal (say, a second
detector current) in response to light provided by optical
resonator 130 at the second resonant wavelength.
[0037] In addition to incorporating detector 140, in some
implementations, bio-sensor chip 110 incorporates a heater 125 and
a calorimeter 135. One such version of bio-sensor chip 110 is shown
in FIG. 2. It should be understood that in variations of the
version illustrated in FIG. 2, one or more elements, such as heater
125, calorimeter 135 and detector 140 for example, can be excluded
from bio-sensor chip 110.
[0038] Furthermore, optical resonator 130 can be fabricated in a
variety of ways. For example (as is shown in FIG. 2), binding site
133 and capture agent 132 can be located upon an external surface
of optical resonator 130 rather than on an internal surface (as
shown in FIG. 1). In general it should be understood that binding
site 133 and capture agent 132 can be located at any other suitable
location with reference to optical resonator 130 as long as this
location permits optical resonator 130 to undergo a shift from a
first resonant wavelength to a second resonant wavelength when a
foreign molecule 131 binds to binding site 133. Such locations
include one that is shown in FIG. 2 in dashed-line outline, where
binding site 133 and capture agent 132 are not in direct contact
with optical resonator 130).
[0039] Heater 125 is used to heat optical resonator 130, and more
particularly in some cases, at least a portion of optical resonator
130 that houses binding site 133. Heating can be carried out for a
variety of reasons. For example, heating can be carried out to
detect and record a thermal response of foreign molecule 131 when
bound to capture agent 132 at binding site 133, and/or to release
foreign molecule 131 from capture agent 132 in order to prepare
binding site 133 to accommodate another foreign molecule 131 (of
the same type, or a different type) as part of a subsequent
diagnostic test.
[0040] When used for recording a thermal response, detector 140
provides data via various electrical signals (for example, detector
currents) that correspond to various resonant wavelengths. The data
may be mapped as a graph of a slope of resonance shift versus time.
Since the slope increases with say, an antigen concentration, a
standard curve can be compiled to calibrate the antigen
concentration over time. The standard curve may then be used to
identify unknown concentration values based on one or more
electrical signals generated in detector 140.
[0041] As pointed out above, detector 140 provides various
advantages for example, in terms of lower cost in comparison to
prior art externally located measurement equipment, and in terms of
increased efficiency and performance as a result of integration
into an implantable package in proximity to optical resonator
130.
[0042] Calorimeter 135 can be used to measure the temperature of
optical resonator 130, or more particularly in some cases, of
binding site 133, when detector 140 is used to generate the various
signals thereby facilitating mapping of the graph described above.
Integrating calorimeter 135 inside bio-sensor chip 110 provides
various advantages, for example, in terms of lower cost in
comparison to prior art externally located calorimeters, and in
terms of increased efficiency and performance as a result of being
located in proximity to optical resonator 130. However, it will be
understood that in some implementations, calorimeter 135 may not be
included in its entirety inside bio-sensor chip 110 but may instead
be located external to bio-sensor chip 110. For example, a
temperature sensor may be located inside bio-sensor chip 110 and a
read-out unit may be located external to bio-sensor chip 110. (It
may also be pertinent to point out that FIGS. 1 and 2 do not show
connectivity and access elements, such as metal tracks, wires,
pins, and connectors, so as to avoid obfuscating the main focus of
the disclosure).
[0043] In general, in accordance with the disclosure, bio-sensor
chip 110 can be fabricated and packaged in a variety of ways in
accordance with a variety of applications. In a first example
application, optical waveguide 120 is fabricated as an optical
fiber (with a suitable coupler/switch 115 placed in-line with the
optical fiber). In a second example application, optical waveguide
120 is fabricated as a groove, a trench, or a rail fabricated upon
say, a semiconductor layer inside an integrated circuit (IC).
Optical resonator 130 can be fabricated as a groove, a trench, a
double-ring, or a protrusion upon the semiconductor layer inside
the IC. When optical resonator 130 is fabricated in this manner,
binding site 133 and capture agent 132 can be located upon any
suitable surface of the groove, trench, double-ring, or protrusion.
Suitable surfaces include one or more internal, external, exposed,
or enclosed surfaces.
[0044] Attention is now drawn to FIG. 3, which shows a first
example embodiment of a probe assembly 300 in accordance with the
present disclosure. This embodiment expands on certain aspects of
needle 155 described above by adding certain other elements to
needle 155 that allow probe assembly 300 adapted for sub-cutaneous
insertion. Specifically, probe assembly 300 includes a subcutaneous
cuff 305 and a peritoneal cuff 320. When probe assembly is inserted
into a living object, such as a human patient, subcutaneous cuff
305 is positioned below outer skin layer 305, while peritoneal cuff
320 is positioned in a peritoneal cavity located inside the living
object.
[0045] Needle 155 may not only house a single bio-sensor chip 110a,
but, in certain applications, may include additional bio-sensor
chips (such as bio-sensor chips 110b and 110c shown in dashed line
outlines).
[0046] FIG. 4 shows a second example embodiment of a probe assembly
400 in accordance with the present disclosure. In contrast to the
needle embodiment described above using FIG. 3, probe assembly 400
is implemented in the form of a catheter 410 that includes
subcutaneous cuff 305 and peritoneal cuff 320. Catheter 410 allows
flexible sub-cutaneous insertion of one or more bio-sensor chips
(110a, 110b and 110c) that may be more suitable for certain types
of applications, such as for example, for testing fluids flowing
through conduits (an IV tube for example). Furthermore, rather than
being limited to "within blood" detection, probe assembly 400 can
be used for testing various types of fluids including dialysates,
water, bicarbonate, and/or in a high glucose concentration inducing
osmotic exchange.
[0047] FIG. 5 shows a third example embodiment of a probe assembly
500 in accordance with the present disclosure. In this embodiment,
probe assembly 525 is a silicon-based bio-sensor assembly that is
insertable into a living object. In other words, probe assembly 525
can be used in place of needle 155 described above with reference
to FIG. 3.
[0048] Probe assembly 525 is fabricated using silicon fabrication
techniques (for example CMOS-based IC fabrication techniques), and
includes an optical resonator and additional elements (such as a
detector, heater, and/or calorimeter) that are all fabricated using
IC fabrication technology. Probe assembly 525 is inserted into a
vein 505 such that a sharp end of probe assembly 525 penetrates
through the outer layer (adventitia 510), the middle layer (media
515), and inner layer (intima 520) before entering the
blood-carrying area of vein 505, whereby blood 530 flows over one
or more optical resonators (not shown) in probe assembly 525. The
flowing blood may carry certain target molecules, for example,
thrombin, which binds to the capture agent provided in the one or
more optical resonators. In this case, the capture agent can be a
suitable aptamer. Multiple measurements may be carried out upon the
flowing blood 530 in order to obtain average measurement values for
example.
[0049] In such an arrangement, wherein probe assembly 525 is
inserted into vein 505, the flowing blood (as well as the use of
heater 125) continuously cleanses contact surfaces of probe
assembly 525, thereby overcoming certain prior art issues wherein
the contact surfaces of the monitoring equipment cause thrombin
levels to change thereby corrupting measurements. The measurements
performed in accordance with the present disclosure can be used for
obtaining average readings of protein by carrying out multiple
measurements over time without withdrawing probe assembly 525 from
vein 505.
[0050] In one example implementation, probe assembly 525 is
provided as a silicon shaft that is 100-500 micrometers wide and
several millimeters long. Miniature waveguides and optical
resonators are defined upon this silicon shaft. The capture agent
can be coated on to the silicon shaft at the binding sites. All or
some of the optical elements of probe assembly 525 can be
lithographically arranged in the silicon shaft through fabrication
processes such as optical or electron beam printing. Furthermore,
probe assembly 525 may contain multiple optical resonators and
detectors configured for detecting multiple analytes that may or
may not be identical to one another.
[0051] FIG. 6 shows an example bio-diagnostic testing application
in accordance with the present disclosure. More particularly, this
example testing application is part of a dialysis procedure wherein
a patient 535 is hooked to a dialysis apparatus 530 via a pair of
tubes. The first tube is a catheter 520 that transports blood from
patient 535 to dialysis apparatus 530 (as indicated by the arrow)
where the blood is processed before being pumped back to patient
535 via a second tube indicted as catheter 510. One or both of
catheters 510 and 520 may include one or more bio-sensor chips.
Furthermore, one or both of catheters 510 and 520 can be inserted
into a peritoneal cavity (for example, a rectouterine pouch or
douglas pouch). The inserted catheters 510 and 520, which can be
cannulated through the skin of patient 535, can be left in place
for various periods of time, including extended periods, such as
several hours, a day, a month, a year, or longer.
[0052] Bio-sensor chip 110a (and any optional additional bio-sensor
chips such as bio-sensor chip 110b) is used to obtain data
pertaining to one or more target molecules (thrombin, for example)
as the blood flows from patient 535 to dialysis apparatus 530.
Similarly, bio-sensor chip 110c (and any optional additional
bio-sensor chips such as bio-sensor chip 110d) is used to obtain
data pertaining to one or more target molecules as the blood flows
from dialysis apparatus 530 back to patient 535. The data so
obtained can be used for example to address dialysis efficiency and
to monitor patient blood quality as a function of time. In one
example bio-diagnostic test, the amount of urea in the blood can be
measured before and after processing in the dialysis apparatus 530
by using data obtained from the various bio-sensor chips.
[0053] As can be understood, the measurements described herein that
can be carried out upon various short-lived molecules (such as
proteins in blood) can be very valuable in the monitoring of
patient 535 during administration of medicine, or during and after,
various kinds of medical procedures. The measurements can be
carried out without time delays (as in prior art techniques) and
the label-free in-vivo measurements avoid contamination of blood
samples and also allow integration of the bio-diagnostic system
into standard medical procedures such as dialysis and intravenous
(IV) operations.
[0054] In conclusion, a bio-diagnostic testing system in accordance
with the present disclosure provides various benefits such as
various packaging formats, low cost manufacturing, low cost use,
in-vivo testing, and improved measurement accuracy and convenience.
The various packaging formats include a needle, a catheter, and a
silicon-based bio-sensor package. Since each of these packages can
be coated with silicone, sterilization of these devices can be
carried out conveniently. Furthermore, the catheter packaging
accommodates a variety of applications such as dialysis operations,
peritoneal operations, and central venous cauterization
operations.
[0055] When bio-diagnostic testing system 100 is configured for
purposes of implanting into an animate object (human being, animal
etc.), some elements can be selectively included inside an
implantable bio-sensor chip 110 while other elements that operate
interactively with bio-sensor chip 110 can be fabricated for use
outside the animate object. Furthermore, it will be understood that
several elements in addition to those described above, can be
incorporated into various embodiments of bio-diagnostic testing
system 100.
[0056] In one such example embodiment, bio-diagnostic testing
system 100 can incorporate a wireless power supply system using
various elements in addition to the elements described above using
the various figures. In such a wireless power system, a transmitter
coil located outside an animate object can be used to transmit
power to a receiver coil implanted inside the animate object. The
receiver coil can be integrated inside bio-sensor chip 110, or can
be a separate element that is placed at a location that is
different than that of bio-sensor chip 110. For example, the
receiver coil can be placed under the skin of the animate object
with suitable wiring connections to bio-sensor chip 110 located
elsewhere (inside a vein, artery, or catheter, for example). The
power provided to bio-sensor chip 110 can be used for directly
powering various elements inside bio-sensor chip 110 (such as
detector 140), or can be used for indirect powering by charging a
rechargeable battery, which in turn provides power to various
elements inside bio-sensor chip 110.
[0057] In another example embodiment, bio-sensor chip 110 can
incorporate a wired power system. In such a wired power system, a
power source located outside the animate object uses wires to
provide power to bio-sensor chip 110. The wires may be placed
inside a dedicated catheter that is dedicated solely for the
purposes of providing power, or in a multi-function catheter that
accommodates multiple functionalities. For example, a
multi-function catheter can carry fluids while simultaneously
housing one or more wires that provide power to bio-sensor chip
110. The wires can provide power to a bio-sensor chip 110 located
inside the animate object and/or a bio-sensor chip 110 located
inside the multi-function catheter itself (as shown in FIG. 4).
[0058] In yet another example embodiment, bio-diagnostic testing
system 100 can incorporate a wireless communication system for
transferring data between bio-sensor chip 110 (implanted inside an
animate object) and one or more communication units located outside
the animate object.
[0059] The wireless communication system can incorporate a
radio-frequency (RF) transmitter inside bio-sensor chip 110. The RF
transmitter wirelessly transmits data, such as data from detector
140, out of the animate object. This data is received by a receiver
in a communication unit located outside the animate object.
[0060] Bio-sensor chip 100 may also include an RF receiver for
receiving signals transmitted from the communication unit located
outside the animate object. These signals can include commands,
controls, or configuration signals.
[0061] All patents and publications mentioned in the specification
may be indicative of the levels of skill of those skilled in the
art to which the disclosure pertains. All references cited in this
disclosure are incorporated by reference to the same extent as if
each reference had been incorporated by reference in its entirety
individually.
[0062] It is to be understood that the disclosure is not limited to
particular methods or systems, which can, of course, vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular embodiments only, and is not
intended to be limiting. As used in this specification and the
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the content clearly dictates otherwise. The
term "plurality" includes two or more referents unless the content
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which the
disclosure pertains.
[0063] The examples set forth above are provided to give those of
ordinary skill in the art a complete disclosure and description of
how to make and use the various embodiments of the disclosure, and
are not intended to limit the scope of what the inventors regard as
their disclosure. Modifications of the above-described modes for
carrying out the disclosure may be used by persons of skill in the
relevant arts, and are intended to be within the scope of the
following claims.
[0064] A number of embodiments of the disclosure have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the present disclosure. Accordingly, other embodiments are
within the scope of the following claims.
* * * * *